The purpose of this project is to understand cytokine regulation in animals infected with Histoplasma Capsulatum. Histoplasmosis is a disease found in certain geographic regions of this country. In a normal host the disease will often be controlled without significant end organ damage. However, patients infected with HIV have a difficulty in eradicating the disease. Therefore it was of interest to study mechanisms which might alter the immune response to this organism with the goal of protecting the animal. Previous work had demonstrated that the organism resides in mononuclear phagocytic cells. Moreover, it was shown that the presence of IFNgamma enables the macrophage to kill the organism. Recently, a new cytokine, IL-12 has been shown to be a potent inducer of IFNgamma from both T cells and NK cells. Thus we set out to investigate the role that IL-12 had in the course of the disease and how it affected cytokine production especially IFNgamma. Mice infected with H. capsulatum and and treated with neutralizing antibodies to IFNgamma, TNFalpha or IL-12 had accelerated mortality, indicating that endogenous production of these cytokines plays an important role in response to infection. In contrast, mice treated with IL-12 or a neutralizing antibody to IL-4 at the initiation of infection had substantially diminished mortality. Moreover, mice infected and treated with IL-12 show a 2-3 fold increase in the amount of IFNgamma following in vitro stimulation with specific H. capsulatum antigen compared to the control infected mice. The protective effect of IL-12 could be abrogated if a neutralizing antibody to IFNgamma was given at the same time, demonstrating that the role of IL-12 in protection was mediated by IFNgamma.